1. Technical Field
This invention is directed to proteinase (protease) inhibitors, and more particularly to aromatic sulfonyl alpha-hydroxy hydroxamic acid compounds that are useful, inter alia, as inhibitors for matrix metalloproteinases, compositions of those compounds, intermediates for the syntheses of the compounds, processes for the preparation of the compounds and processes for treating pathological conditions associated with pathological matrix metalloproteinase activity.
2. Background of the Invention
Connective tissue, extracellular matrix constituents and basement membranes are required components of all mammals. These components are the biological materials that provide rigidity, differentiation, attachments and, in some cases, elasticity to biological systems including human beings and other mammals. Connective tissues components include, for example, collagen, elastin, proteoglycans, fibronectin and laminin. These biochemicals make up, or are components of structures, such as skin, bone, teeth, tendon, cartilage, basement membrane, blood vessels, cornea and vitreous humor.
Under normal conditions, connective tissue turnover and/or repair processes are controlled and in equilibrium. The loss of this balance for whatever reason is involved in a number of disease states. Inhibition of the enzymes responsible for a loss of equilibrium provides a control mechanism for this tissue decomposition and, therefore, a treatment for these diseases.
Degradation of connective tissue or connective tissue components is carried out by the action of proteinase enzymes released from resident tissue cells and/or invading inflammatory or tumor cells. A major class of enzymes involved in this function are the zinc metalloproteinases (metalloproteases, or MMPs).
The metalloprotease enzymes are divided into classes with some members having several different names in common use. Examples are: collagenase I (MMP-1, fibroblast collagenase; EC 3.4.24.3); collagenase II (MMP-8, neutrophil collagenase; EC 3.4.24.34), collagenase III (MMP-13), stromelysin 1 (MMP-3; EC 3.4.24.17), stromelysin 2 (MMP-10; EC 3.4.24.22), proteoglycanase, matrilysin (MMP-7), gelatinase A (MMP-2, 72 kDa gelatinase, basement membrane collagenase; EC 3.4.24.24), gelatinase B (MMP-9, 92 kDa gelatinase; EC 3.4.24.35), stroinelysin 3 (MMP-11), metalloelastase (MMP-12, HME, human macrophage elastase) and membrane MMP (MMP-14). MMP is an abbreviation or acronym representing the term Matrix Metalloprotease with the attached numerals providing differentiation between specific members of the MMP group.
The uncontrolled breakdown of connective tissue by metalloproteases is a feature of many pathological conditions. Examples include rheumatoid arthritis, osteoarthritis, septic arthritis; corneal, epidermal or gastric ulceration; tumor metastasis, invasion or angiogenesis; periodontal disease; proteinuria; multiple sclerosis; Alzheimer""s Disease; coronary thrombosis and bone disease. Defective injury repair processes can also occur. This can produce improper wound healing leading to weak repairs, adhesions and scarring. These latter defects can lead to disfigurement and/or permanent disabilities as with post-surgical adhesions.
Matrix metalloproteases are also involved in the biosynthesis of tumor necrosis factor (TNF) and inhibition of the production or action of TNF and related compounds is an important clinical disease treatment mechanism. TNF-xcex1, for example, is a cytokine that at present is thought to be produced initially as a 28 kD cell-associated molecule. It is released as an active, 17 kD form that can mediate a large number of deleterious effects in vitro and in vivo. For example, TNF can cause and/or contribute to the effects of inflammation, rheumatoid arthritis, autoimmune disease, multiple sclerosis, graft rejection, fibrotic disease, cancer, infectious diseases, malaria, mycobacterial infection, meningitis, fever, psoriasis, cardiovascular/pulmonary effects such as post-ischemic reperfusion injury, congestive heart failure, hemorrhage, coagulation, hyperoxic alveolar injury, radiation damage and acute phase responses like those seen with infections and sepsis and during shock such as septic shock and hemodynamic shock. Chronic release of active TNF can cause cachexia and anorexia. TNF can be lethal.
TNF-xcex1 convertase is a metalloproteinase involved in the formation of active TNF-xcex1. Inhibition of TNF-xcex1 convertase inhibits production of active TNF-xcex1. Compounds that inhibit both MMPs activity have been disclosed in WIPO International Publication Nos. WO 94/24140, WO 94/02466 and WO 97/20824. There remains a need for effective MMP and TNF-xcex1 convertase inhibiting agents. Compounds that inhibit MMPs such as collagenase, stromelysin and gelatinase have been shown to inhibit the release of TNF (Gearing et al. Nature 376, 555-557 (1994), McGeehan et al., Nature 376, 558-561 (1994)).
MMPs are involved in other biochemical processes in mammals as well. Included is the control of ovulation, post-partum uterine involution, possibly implantation, cleavage of APP (xcex2-Amyloid Precursor Protein) to the amyloid plaque and inactivation of xcex11-protease inhibitor (xcex11-PI). Inhibition of these metalloproteases permits the control of fertility and the treatment or prevention of Alzheimers Disease. In addition, increasing and maintaining the levels of an endogenous or administered serine protease inhibitor drug or biochemical such as xcex11-PI supports the treatment and prevention of diseases such as emphysema, pulmonary diseases, inflammatory diseases and diseases of aging such as loss of skin or organ stretch and resiliency.
Inhibition of selected MMPs can also be desirable in other instances. Treatment of cancer and/or inhibition of metastasis and/or inhibition of angiogenesis are examples of approaches to the treatment of diseases wherein the selective inhibition of stromelysin (MMP-3), gelatinase (MMP-2), gelatinase B (MMP-9) or collagenase III (MMP-13) are the relatively most important enzyme or enzymes to inhibit especially when compared with collagenase I (MMP-1). A drug that does not inhibit collagenase I can have a superior therapeutic profile. Osteoarthritis. another prevalent disease wherein it is believed that cartilage degradation in inflamed joints is at least partially caused by MMP-13 released from cells such as stimulated chrondrocytes, may be best treated by administration of drugs one of whose modes of action is inhibition of MMP-13. See, for example, Mitchell et al., J. Clin. Invest., 97:761-768 (1996) and Reboul et al., J. Clin. Invest., 97:2011-2019 (1996).
Inhibitors of metalloproteases are known. Examples include natural biochemicals such as tissue inhibitor of metalloproteinase (TIMP), xcex12-macroglobulin and their analogs or derivatives. These are high molecular weight protein molecules that form inactive complexes with metalloproteases. A number of smaller peptide-like compounds that inhibit metalloproteases have been described. Mercaptoamide peptidyl derivatives have shown ACE inhibition in vitro and in vivo. Angiotensin converting enzyme (ACE) aids in the production of angiotensin II, a potent pressor substance in mammals and inhibition of this enzyme leads to the lowering of blood pressure.
Thiol group-containing amide or peptidyl amide-based metalloprotease (MMP) inhibitors are known as is shown in, for example, WO95/12389, WO96/11209 and U.S. Pat. No. 4,595,700. Hydroxamate group-containing MMP inhibitors are disclosed in a number of published patent applications such as WO 95/29892, WO 97/24117, WO 97/49679 and EP 0 780 386 that disclose carbon back-boned compounds, and WO 90/05719, WO 93/20047, WO 95/09841 and WO 96/06074 that disclose hydroxamates that have a peptidyl back-bones or peptidomimetic back-bones, as does the article by Schwartz et al., Progr. Med. Chem., 29:271-334(1992) and those of Rasmussen et al., Pharmacol. Ther., 75 (1): 69-75 (1997) and Denis et al., Invest. New Drugs, 15(3): 175-185 (1997).
One possible problem associated with known MMP inhibitors is that such compounds often exhibit the same or similar inhibitory effects against each of the MMP enzymes. For example, the peptidomimetic hydroxamate known as batimastat is reported to exhibit IC50 values of about 1 to about 20 nanomolar (nM) against each of MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9. Marimastat, another peptidomimetic hydroxamate was reported to be another broad-spectrum MMP inhibitor with an enzyme inhibitory spectrum very similar to batimastat, except that marimastat exhibited an IC50 value against MMP-3 of 230 nM. Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997).
Meta analysis of data from Phase I/II studies using marimastat in patients with advanced, rapidly progressive, treatment-refractory solid tumor cancers (colorectal, pancreatic, ovarian, prostate) indicated a dose-related reduction in the rise of cancer-specific antigens used as surrogate markers for biological activity. Although marimastat exhibited some measure of efficacy via these markers, toxic side effects were noted. The most common drug-related toxicity of marimastat in those clinical trials was musculoskeletal pain and stiffness, often commencing in the small joints in the hands, spreading to the arms and shoulder. A short dosing holiday of 1-3 weeks followed by dosage reduction permits treatment to continue. Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997). It is thought that the lack of specificity of inhibitory effect among the MMPs may be the cause of that effect.
In view of the importance of hydroxamate MMP inhibitor compounds in the treatment of several diseases and the lack of enzyme specificity exhibited by two of the more potent drugs now in clinical trials, it would be a great benefit if hydroxamates of greater enzyme specificity could be found. This would be particularly the case if the hydroxamate inhibitors exhibited strong inhibitory activity against one or more of MMP-2, MMP-9 or MMP-13 that are associated with several pathological conditions, while at the same time exhibiting limited inhibition of MMP-1, an enzyme that is relatively ubiquitous and known to participate in a number of homeostatic processes. The disclosure that follows describes one family of hydroxamate MMP inhibitors that exhibit those desirable activities.
The present invention is directed to a family of molecules that inter alia inhibit matrix metalloprotease (MMP) activity, and particularly inhibit the activity of one or more of MMP-2, MMP-9, or MMP-13, while generally exhibiting little activity against MMP-1, as well as a process for treating a mammal having a condition associated with pathological activity.
Briefly, one embodiment of the present invention is directed to an aromatic sulfonyl alpha-hydroxy hydroxamic acid compound. That compound corresponds in structure to Formula I. 
wherein
R2 is a hydrido, C1-C4 hydrocarbyl, hydroxy-C1-C4 hydrocarbyl, C1-C4 hydrocarbyloxy, halo-C1-C4 hydrocarbyl, C1-C4 hydrocarbyloxymethyl, aminomethyl, (Nxe2x80x94C1-C3 hydrocarbyl)aminomethyl, (N,N-di-C1-C3 hydrocarbyl)aminomethyl, (N-morpholino)methyl, (N-pyrrolidino)methyl, or (N-thiomorpholino)methyl group. R2 is preferably a hydrido, hydroxy, hydroxymethyl, methoxymethyl or methyl-N-morpholinyl group.
R1 is a substituent that contains a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted SO2-group and having a length greater than about that of a fully extended hexyl group and less than about that of a fully extended eicosyl group. In addition, R1 defines a three-dimensional volume, when rotated about an axis drawn through the SO2-bonded 1-position and the 4-position of a 6-membered ring radical or drawn through the SO2-bonded 1-position and the center of 3,4-bond of a 5-membered ring radical, whose widest dimension in a direction transverse to the axis of rotation is about that of one furanyl ring to about that of two phenyl rings.
R1 preferably contains a single aromatic or heteroaromatic ring that is itself substituted with another substituent, R3. R1 most preferably contains a phenyl ring, Ph, that is itself has a substituent, R3, at the 4-position. R3 is preferably a phenyl, a phenoxy, a phenylazo, a thiophenoxy, an anilino, a benzamido, a nicotinamido, an isonicotinamido, a picolinamido or an ureidophenyl group that can itself be substituted at the meta- or para-position or both by a single atom or a substituent containing a longest chain of up to eight atoms, excluding hydrogen.
A process for treating a host mammal having a condition associated with pathological matrix metalloprotease activity is also contemplated. That process comprises administering a compound described hereinbefore in an enzyme-inhibiting effective amount to a mammalian host having such a condition. The use of repeated administrations is particularly contemplated.
Among the several benefits and advantages of the present invention are the provision of compounds and compositions effective as inhibitors of matrix metalloproteinase activity, and the provision of such compounds and compositions that are effective for the inhibition of metalloproteinases implicated in diseases and disorders involving uncontrolled breakdown of connective tissue.
More particularly, a benefit of this invention is the provision of a compound and composition effective for inhibiting metalloproteinases, particularly MMP-13 and/or MMP-2, associated with pathological conditions such as, for example, rheumatoid arthritis, osteoarthritis, septic arthritis; corneal, epidermal or gastric ulceration; tumor metastasis, invasion or angiogenesis; periodontal disease; proteinuria; multiple sclerosis; Alzheimer""s Disease; coronary thrombosis and bone disease.
An advantage of the invention is the provision of a method for preparing such compositions. Another benefit is the provision of a method for treating a pathological condition associated with abnormal matrix metalloproteinase activity.
Another advantage of the invention is the provision of compounds, compositions and methods effective for treating such pathological conditions by selective inhibition of a metalloproteinase such as MMP-13 and MMP-2 associated with such conditions with minimal side effects resulting from inhibition of other proteinases such as MMP-1, whose activity is necessary or desirable for normal body function.
Still further benefits and advantages of the invention will be apparent to the skilled worker from the disclosure that follows.
In accordance with the present invention, it has been found that certain aromatic sulfonyl alpha-hydroxy hydroxamic acids (hydroxamates) are effective for inhibition of matrix metalloproteinases (xe2x80x9cMMPsxe2x80x9d) believed to be associated with uncontrolled or otherwise pathological breakdown of connective tissue. In particular, it has been found that these certain aromatic sulfonyl alpha-hydroxy hydroxamic acids are effective for inhibition of collagenase III (MMP-13) and also gelatinase A (MMP-2), which can be particularly destructive to tissue if present or generated in abnormal quantities or concentrations, and thus exhibit a pathological activity.
Moreover, it has been discovered that many of these aromatic sulfonyl alpha-hydroxy hydroxamic acids are selective in the inhibition of MMP-13, as well as other MMPs associated with diseased conditions without excessive inhibition of other collagenases essential to normal bodily function such as tissue turnover and repair. More particularly, at has been found that particularly preferred the aromatic sulfonyl alpha-hydroxy hydroxamic acids are particularly active in inhibiting of MMP-13 and MMP-2, while having a limited or minimal effect on MMP-1. This point is discussed in detail hereinafter and is illustrated in the Inhibition Tables hereinafter.
A contemplated compound corresponds to Formula I, below: 
wherein
R2 is a hydrido, C1-C4 hydrocarbyl, hydroxy-C1-C4 hydrocarbyl, C1-C4 hydrocarbyloxy, halo-C1-C4 hydrocarbyl, C1-C4 hydrocarbyloxymethyl, aminomethyl (NH2CH2xe2x80x94), (N-C1-C3 hydrocarbyl)aminomethyl, (N,N-di-C1-C3 hydrocarbyl)aminomethyl [(N-C1-C3 hydrocarbyl) (N-C1-C3 hydrocarbyl) aminomethyl], (N-morpholino)methyl (OC4H8NCH2xe2x80x94), (N-pyrrolidino)methyl (C4H8NCH2xe2x80x94), or (N-thiomorpholino)methyl (SC4H8NCH2xe2x80x94) group. In particularly preferred practice, R2 substituent is a methyl, hydroxymethyl, (N-morpholino)methyl or methoxymethyl group. R1 is a substituent containing a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted SO2-group and having a length equivalent to a length that is greater than about that of a fully extended hexyl group and less than about that of a fully extended eicosyl group. In addition, R1 defines a three-dimensional volume, when rotated about an axis drawn through the SO2-bonded 1-position and the 4-position of a 6-membered ring radical or drawn through the SO2-bonded 1-position and the center of 3,4-bond of a 5-membered ring radical, whose widest dimension in a direction transverse to the axis of rotation is about that of one furanyl ring to about that of two phenyl rings.
As noted above, an R1 substituent contains a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted SO2-group. An R1 substituent also has length, width and substitution requirements that are discussed in detail below. It is noted here, however, that a single-ringed or fused ring cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is not itself long enough to fulfill the length requirement. As such, that cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical must itself be substituted.
Exemplary 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radicals that can constitute a portion of a R1 substituent and are themselves substituted as discussed herein include phenyl, 2-, 3-, or 4-pyridyl, 2-naththyl, 2-pyrazinyl, 2- or 5-pyrimidinyl, 2- or 3-benzo(b)thienyl, 8-purinyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-imidazolyl, cyclopentyl, cyclohexyl, 2- or 3-piperidinyl, 2- or 3-morpholinyl, 2- or 3-tetrahydropyranyl, 2-imidazolidinyl, 2- or 3-pyrazolidinyl and the like. A phenyl radical is particularly preferred and is used illustratively herein.
When examined along its longest chain of atoms, an R1 substituent, including its own substituent when present, has a total length that is greater than that of a fully extended saturated chain of six carbon atoms (a hexyl group); i.e., a length of a heptyl chain or longer, and a length that is less than that of a fully extended saturated chain of about 20 carbons (an eicosyl group). Preferably, that length is equivalent to that of a fully extended saturated chain of about 8 to about 18 carbon atoms, even though many more atoms may be present in the actual ring structures or substituents. This length requirement is discussed further below.
Looked at more generally, and aside from specific moieties from which it is constructed, an R1 substituent (radical, group or moiety) has a length that is equivalent to that of a fully extended heptyl group or greater. Such an R1 substituent also has a length that is less than that of a fully extended eicosyl group. That is to say that a R1 is a substituent having a length greater than that of an extended saturated six carbon chain and shorter than that of an extended saturated eighteen carbon chain, and more preferably, a length greater than that of an octyl group and less than that of a palmityl group. The radical chain lengths are measured along the longest linear atom chain in the radical, following the skeletal atoms of a ring where necessary. Each atom in the chain, e.g. carbon, oxygen or nitrogen, is presumed to be carbon for ease in calculation.
Such lengths can be readily determined by using published bond angles, bond lengths and atomic radii, as needed, to draw and measure a chain, or by building models using commercially available kits whose bond angles, lengths and atomic radii are in accord with accepted, published values. Radical (substituent) lengths can also be determined somewhat less exactly by presuming, as is done here, that all atoms have bond lengths of saturated carbon, that unsaturated and aromatic bonds have the same lengths as saturated bonds and that bond angles for unsaturated bonds are the same as those for saturated bonds, although the above-mentioned modes of measurement are preferred. For example, a 4-phenyl or 4-pyridyl group has a length of a four carbon chain, as does a propoxy group, whereas a biphenyl group has a length of about an eight carbon chain using a contemplated measurement mode.
In addition, an R1 substituent, when rotated about an axis drawn through the SO2-bonded 1-position and the 4-position of a 6-membered ring radical or the SO2-bonded 1-position and through the 3,4 bond of a 5-membered ring radical defines a three-dimensional volume whose widest dimension has the width of about one furanyl ring to about the width of two phenyl rings in a direction transverse to that axis to rotation.
When utilizing this width or volume criterion, a fused ring system such as a naphthyl or purinyl radical is considered to be a 6- or 5-membered ring that is substituted at appropriate positions numbered from the SO2-linkage that is deemed to be at the 1-position as discussed before. Thus, a 2-naphthyl substituent or an 8-purinyl substituent is an appropriately sized R1 radical as to width when examined using the above rotational width criterion. On the other hand, a 1-naphthyl group or a 7- or 9-purinyl group is too large upon rotation and is excluded.
As a consequence of these length and width requirements, R1 substituents such as 4-(phenyl)phenyl [biphenyl], 4-(4xe2x80x2-methoxyphenyl)phenyl, 4-(phenoxy)phenyl, 4-(thiophenyl)phenyl [4-(phenylthio)phenyl], 4-(phenylazo)phenyl 4-(ureidophenyl)phenyl, 4-(anilino)phenyl, 4-(nicotinamido)phenyl, 4-(isonicotinamido)phenyl, 4-(picolinamido)phenyl and 4-(benzamido)phenyl are among particularly preferred R1 substituents, with 4-(phenoxy)phenyl and 4-(thiophenyl)phenyl being most preferred.
An SO2-linked cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is a 5- or 6-membered single-ring that is itself substituted with one other substituent, R3. The SO2-linked single-ringed cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is R3-substituted at its own 4-position when a 6-membered ring and at its own 3-position when a 5-membered ring. The cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical to which R3 is bonded is preferably a phenyl group, so that R1 is preferably PhR3 in which R3 is bonded at the 4-position of the SO2-linked phenyl (Ph) radical, and in which R3 can itself be optionally substituted as is discussed hereinafter. Substitution at the 2-position of a SO2-linked cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical appears to greatly lessen inhibitory potency toward MMP enzymes, and is absent from a contemplated compound.
A contemplated R3 substituent can be a single-ringed cyclohydrocarbyl, heterocyclo, aryl or heteroaryl group or another substituent having a chain length of 3 to about 14 carbon atoms such as a hydrocarbyl or hydrocarbyloxy group [e.g., C3-C14 hydrocarbyl or Oxe2x80x94C2-C14 hydrocarbyl], a phenyl group, a phenoxy group [xe2x80x94OC6H5], a thiophenoxy group [phenylsulfanyl; xe2x80x94SC6H5], an anilino group [xe2x80x94NHC6H5], a phenylazo group [xe2x80x94N2C6H5], an ureidophenyl group (aniline carbonylamino; xe2x80x94NHC(O)NHxe2x80x94C6H5], a benzamido group [xe2x80x94NHC(O)C6H5], a nicotinamido group [3NHC(O)C5H4N], an isonicotinamido group [4NHC(O)C5H4N], or a picolinamido group [2NHC(O)C5H4N]. As noted before in conjunction with the discussion of R1, most preferred R3 substituents are phenoxy and thiophenoxy groups that are preferably themselves free of substitution. Additionally contemplated R3 substituent groups include a heterocyclo, heterocyclohydrocarbyl, arylhydrocarbyl, arylheterocyclohydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroarylhydrocarbylamino, or a heteroarylthio group.
A contemplated R3 substituent can itself also be substituted with one or more substituent radicals at the meta- or para-position or both of a six-membered ring with a single atom or a substituent containing a longest chain of up to ten atoms, excluding hydrogen. Exemplary substituent radicals include a halo, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclic, heteroaryl, hydroxycarbonyl-hydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxy-carbonylhydrocarbyl, hydrocarbylhydroxycarbonyl-hydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbyl-sulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino and N-monosubstituted or N,N-disubstituted aminohydrocarbyl group wherein the substituent(s) on the nitrogen are selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring group.
Thus, initial studies indicate that so long as the length, substitution and width (volume upon rotation) requirements of an SO2-linked R1 substituent discussed herein are met, an R1 substituent can be extremely varied.
A particularly preferred R3 substituent of an SO2-linked Ph group is a single-ringed aryl or heteroaryl, phenoxy, thiophenoxy, phenylazo, ureidophenyl, nicotinamido, isonicotinamido, picolinamido, anilino or benzamido group that is unsubstituted or is itself substituted (optionally substituted) at the para-position when a 6-membered ring or the 3-position when a 5-membered ring. Here, single atoms such as halogen moieties or substituents that contain one to a chain of about ten atoms other than hydrogen such as C1-C10 hydrocarbyl, C1-C9 hydrocarbyloxy or carboxyethyl groups can be used.
Exemplary particularly preferred substituted PhR3 (particularly preferred substituted R1) substituents include biphenyl, 4-phenoxyphenyl, 4-thiophenoxyphenyl, 4-benzamidophenyl, 4-ureidophenyl, 4-anilinophenyl, 4-nicotinamido, 4-isonicotinamido, and 4-picolinamido. Exemplary particularly preferred R3 groups contain a 6-membered aromatic ring and include a phenyl group, a phenoxy group, a thiophenoxy group, a phenylazo group, an ureidophenyl group, an anilino group, a nicotinamido group, an isonicotinamido group, a picolinamido group and a benzamido group.
More specifically, a particularly preferred sulfonyl butanhydroxamate compounds has an R3 substituent that is a phenyl group, a phenoxy group, a thiophenoxy group, a phenylazo group, an ureidophenyl group, an anilino group, a nicotinamido group, an isonicotinamido group, a picolinamido group or a benzamido group that is itself optionally substituted at its own meta or para-position or both with a moiety that is selected from the group consisting of a halogen, a C1-C9 hydrocarbyloxy (xe2x80x94Oxe2x80x94C1-C9 hydrocarbyl) group, a C1-C10 hydrocarbyl group, a di-C1-C9 hydrocarbylamino [xe2x80x94N(C1-C9 hydrocarbyl)(C1-C9 hydrocarbyl)] group, a carboxyl C1-C8 hydrocarbyl (C1-C8 hydrocarbyl-CO2H) group, a C1-C4 hydrocarbyloxy carbonyl C1-C4 hydrocarbyl [C1-C4 hydrocarbyl-Oxe2x80x94(CO)-C1-C4 hydrocarbyl]group, a C1-C4 hydrocarbyloxycarbonyl C1-C4 hydrocarbyl [C1-C4 hydrocarbyl(CO)xe2x80x94Oxe2x80x94C1-C4 hydrocarbyl] group and a C1-C8 hydrocarbyl carboxamido [xe2x80x94NH(CO)-C1-C8 hydrocarbyl] group, or is substituted at the meta- and para-positions by two methyl groups or by a C1-C2 alkylenedioxy group such as a methylenedioxy group.
Inasmuch as a contemplated SO2-linked cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is itself preferably substituted with a 6-membered aromatic ring, two nomenclature systems are used together herein for ease in understanding substituent positions. The first system uses position numbers for the ring directly bonded to the SO2-group, whereas the second system uses ortho, meta or para for the position of one or more substituents of a 6-membered ring bonded to a SO2-linked cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical. When a R3 substituent is other than a 6-membered ring, substituent positions are numbered from the position of linkage to the aromatic or heteroaromatic ring. Formal chemical nomenclature is used in naming particular compounds.
Thus, the 1-position of an above-discussed SO2-linked cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is the position at which the SO2-group is bonded to the ring. The 4- and 3-positions of rings discussed here are numbered from the sites of substituent bonding from the SO2-linkage as compared to formalized ring numbering positions used in heteroaryl nomenclature.
In particularly preferred practice, R1 contains a phenyl group (Ph) linked at its own 4-position to another substituent, R3, so that R1 is PhR3, and a contemplated compound has a structure that corresponds to Formula II, below, wherein R2 is as before defined and R3 is as defined below. 
A particularly preferred R3 substituent of an SO2-linked Ph group is a single-ringed aryl or heteroaryl, phenoxy, thiophenoxy, phenylazo, ureidophenyl, nicotinamido, isonicotinamido, picolinamido, anilino or benzamido group that is unsubstituted or is itself substituted (optionally substituted) at the para-position when a six-membered ring or the 3-position when a five-membered ring. Here, single atoms such as halogen moieties or substituents that contain one to a chain of about ten atoms other than hydrogen such as C1-C10 hydrocarbyl, C1-C9 hydrocarbyloxy or carboxyethyl groups can be used.
Exemplary particularly preferred substituted R1 PhR3 substituents include biphenyl, 4-phenoxyphenyl, 4-thiophenoxyphenyl, 4-benzamidophenyl, 4-ureidophenyl, 4-anilinophenyl, 4-nicotinamido, 4-isonicotinamido, and 4-picolinamido. Exemplary particularly preferred R3 groups contain a six-membered aromatic ring and include a phenyl group, a phenoxy group, a thiophenoxy group, a phenylazo group, an ureidophenyl group, an anilino group, a nicotinamido group, an isonicotinamido group, a picolinamido group and a benzamido group.
In one embodiment of a particularly preferred aromatic sulfonyl alpha-hydroxy hydroxamate compound, an R3 substituent is a phenyl, phenoxy, anilino or thiophenoxy group that is itself optionally substituted at its own meta or para-position or both with a moiety that is selected from the group consisting of a halogen, a C1-C9 hydrocarbyloxy (xe2x80x94Oxe2x80x94C1-C9 hydrocarbyl) group, a C1-C10 hydrocarbyl group, a di-C1-C9 hydrocarbylamino [xe2x80x94N(C1-C9 hydrocarbyl)(C1-C9 hydrocarbyl)] group, a carboxyl C1-C8 hydrocarbyl (C1-C8 hydrocarbyl-CO2H) group, a C1-C4 hydrocarbyloxy carbonyl C1-C4 hydrocarbyl [C1-C4 hydrocarbyl-Oxe2x80x94(CO)xe2x80x94C1-C4 hydrocarbyl] group, a C1-C4 hydrocarbyloxycarbonyl C1-C4 hydrocarbyl [C1-C4 hydrocarbyl(CO)xe2x80x94Oxe2x80x94C1-C4 hydrocarbyl] group and a C1-C8 hydrocarbyl carboxamido [xe2x80x94NH(CO)xe2x80x94C1-C8 hydrocarbyl] group, or is substituted at the meta- and para-positions by two methyl groups or by a C1-C2 alkylenedioxy group such as a methylenedioxy group. These compounds generally exhibit good activities (IC50 values of about 0.1-60 nM) against MMP-2, MMP-9 and MMP-13, while exhibiting substantially less activity toward MMP-1 (IC50 values of about 1000 to  greater than 10,000 nM). An unsubstituted phenoxy or thiophenoxy R3 substituent is presently preferred.
In another embodiment of a particularly preferred aromatic sulfonyl alpha-hydroxy hydroxamate compound, a R3 substituent is benzamido, nicotinamido, isonicotinamido, picolinamido or ureidophenyl in which the substituent ring (benzamido, nicotinamido, isonicotinamido, picolinamido or ureidophenyl group) is unsubstituted or is itself (optionally) substituted at its own metaor para-position. A preferred substituent moiety on the substituent ring is selected from the group consisting of a halogen, a nitro, a C1-C8 hydrocarbyl, C1-C7 hydrocarbyloxy, a C1-C2 alkylenedioxy, an amino, an Nxe2x80x94C2-C4-hydroxyalkyl-amino [e.g., xe2x80x94NH(C4H8OH)] and an N,N-C2-C4-hydroxyalkylamino [e.g., xe2x80x94N(C2H4OH)2] group. Some of these compounds exhibit more than a 100,000-fold difference in in vitro inhibitory activity against MMP-2 and MMP-1, and an about 2- to about 100-fold activity enhancement against MMP-2 over MMP-13, while still maintaining nanomolar activity against MMP-2. These compounds exhibited about a 10- to about 100-fold activity difference between MMP-2 and MMP-9. Such compounds illustrate one aspect of the activity and selectivity of inhibition of some of the contemplated compounds.
Inasmuch as a contemplated SO2-linked aryl or heteroaryl radical is itself preferably substituted with a six-membered aromatic ring, two nomenclature systems are used together herein for ease in understanding substituent positions. The first system uses position numbers for the ring directly bonded to the SO2-group, whereas the second system uses ortho, meta or para for the position of one or more substituents of a six-membered ring bonded to a SO2-linked aryl or heteroaryl radical. When a R3 substituent is other than a six-membered ring, substituent positions are numbered from the position of linkage to the aromatic or heteroaromatic ring. Formal chemical nomenclature is used in naming particular compounds.
Thus, the 1-position of an above-discussed SO2-linked aryl or heteroaryl radical is the position at which the SO2-group is bonded to the ring. The 4-and 3-positions of rings discussed here are numbered from the sites of substituent bonding from the SO2-linkage as compared to formalized ring numbering positions used in heteroaryl nomenclature.
The length, width and the number of aromatic rings present in a R1 substituent bonded to the SO2 group is believed to play a role in the overall activity of a contemplated compound against MMP enzymes generally. The identity of the R1 substituent group can also play a role in the activity of an compound against particular MMP enzymes. In addition, substitution at the alpha-position to the hydroxamic acid group; i.e., substitution on the carbon atom between the hydroxamic acid group and the methylene-SO2 group, also appears to play a role in the specificity of a contemplated compound as an inhibitor of specific a MMP enzyme.
For example, the compound of Example 8 [N,2-dihydroxy-3-[(4-methoxyphenyl)sulfonyl]propanamide] whose SO2-bonded aryl group is a 4-methoxyphenyl substituent having a length of about a six carbon chain (a hexyl group) was found to be relatively inactive as an inhibitor of MMP-1 and only slightly better against MMP-13. That lack of activity can be compared to the excellent activity exhibited by the compound of Example 9 [N,2-dihydroxy-3-[(4-phenoxyphenyl)sulfonyl]-propanamide that is substituted similarly at the alpha-position, but has a longer R1 group (an about nine carbon chain). These comparative activities can be seen in Table 51 hereinafter.
The compounds of Examples 14-35 contain PhR3 R1 groups that include an amido [xe2x80x94C(O)NHxe2x80x94] functionality as part of the R1 group. Those R1 groups, depending upon the total length of R1, appear to somewhat lessen the activity of the compounds toward MMP-13, while virtually eliminating any activity against MMP-1, and thus provide exquisite specificity in distinguishing between those two enzymes. This phenomenon appears to hold whether the R3 group contains an aromatic moiety or an aliphatic moiety bonded to the amido group and whether the amido group is present as a xe2x80x94C(O)NHxe2x80x94 linkage or part of a ureido [xe2x80x94NHC(O)NHxe2x80x94] linkage. It thus appears as though compounds that contain an amido group-containing R1 substituent are bound minimally, if at all, by MMP-1. These data are also shown in Table 51 hereinafter.
Those data of Table 51 also show the relative importance of overall length of the R1 substituent as well as the relative benefit of that substituent having two aromatic rings. Thus, the compound of Example 24 [4-(heptyloxy)xe2x80x94N-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]benzamide], whose R1 group has a length of about an 18-carbon chain exhibited potencies against MMP-13 and MMP-2 that were greater than could be measured in the assay, and an activity against MMP-1 that was lower than could be measured in the assay. Comparison of the data in Table 51 for the compounds of Examples 16 and 17 {N-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]-sulfonyl]phenyl]benzamide and N-[4-[[2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]sulfonyl]phenyl]-3-methylbutanamide] for compounds whose R1 groups are almost the same length shows the compound with two aromatic rings to be more active.
It is also preferred that the R1 substituent contain a thioether linkage, as is present in a thiophenoxy R3 group. This preference can be seen by comparison of the activities in Table 51 of similarly substituted compounds whose R1 groups differ in the presence or absence of a thioether group as in the compounds of Examples 2 and 13 or 9 and 12.
A contemplated matrix compound contains an asymmetric carbon atom at the alpha-position so that enantiomeric, d and l or R and S, forms of each compound exist. Particularly preferred stereoconfigurations for a contemplated enantiomeric compound are shown below in Formulas III and IV 
In the above formulas, the dashed line represents a bond that extends beneath the plane of the page, whereas the solid wedge-shaped line represents a bond that extends above the plane of the page, as is usual in stereochemical depictions. Where the R2 group is methyl, a contemplated compound of Formulas III or IV have the S stereoconfiguration.
Examination of X-ray crystallographic data of a complex of a contemplated compound bound to MMP-8, an enzyme which is quite similar to MMP-13, indicates that an intramolecular hydrogen bond is formed between the alpha-hydroxyl group and a sulfonyl group oxygen of an compound having the stereoconfiguration shown in Formulas III or IV. The observation of this hydrogen bond was unexpected. The conformation of the bound inhibitor (Example 1A) appears to allow the intramolecular hydrogen bond for only this stereoisomer. That hydrogen bond cannot form from a compound of the opposite configuration while maintaining (a) the orientation of the hydroxamate group toward the metal ion of the enzyme and (b) the position of the R1 group in the binding pocket of the enzyme. This may account for the better binding of this compound to MMP-13, -2 and -9, compared to a compound of the opposite configuration (compound of Example 1B) (See Table 51 for enzyme data).
Intramolecular hydrogen bonds are well known to those skilled in the art. Although the S stereoisomer of Example 1A is preferred, both configurations permit this favorable intramolecular interaction in solution. The advantages of such intramolecular hydrogen-bonding for medicaments have been reported by several research groups. See, for example, Smith, et al. J. med. Chem. (1994) 37(2), 215-218 and Leone-Bay et al. J. Med. Chem. (1996) 39(13), 2571-2578.
The data shown in Table 51 illustrate better binding for a compound of the above configuration (compound of Example 1A) to MMP-13, -2 and -9 than a compound of the opposite configuration (compound of Example 1B). Binding of both compounds to MMP-1 was within about a factor of ten. However, because of the better binding of the compound of Example 1A to MMP-13, the ratio of inhibition of MMP-1 to inhibition of MMP-13 was about 2-times greater for the compound of the above stereoconfiguration (Exhibit 1A compound) than for the compound of opposite configuration. The advantages of such intramolecular hydrogen-bonding for medicaments have been reported by several research groups. See, for example, Smith, et al., J. Med. Chem. (1994) 37(2), 215-218 and Leone-Bay et al., J. Med. Chem. (1996) 39(13), 2571-2578.
The word xe2x80x9chydrocarbylxe2x80x9d is used herein as a short hand term to include straight and branched chain aliphatic as well as alicyclic groups or radicals that contain only carbon and hydrogen. Thus, alkyl, alkenyl and alkynyl groups are contemplated, whereas aromatic hydrocarbons such as phenyl and naphthyl groups, which strictly speaking are also hydrocarbyl groups, are referred to herein as aryl groups or radicals, as discussed hereinafter. Where a specific aliphatic hydrocarbyl substituent group is intended, that group is recited; i.e., C1-C4 alkyl, methyl or dodecenyl. Exemplary hydrocarbyl groups contain a chain of 1 to about 12 carbon atoms, and preferably one to about 10 carbon atoms. A particularly preferred hydrocarbyl group is an alkyl group.
Usual chemical suffix nomenclature is followed when using the word xe2x80x9chydrocarbylxe2x80x9d except that the usual practice of removing the terminal xe2x80x9cylxe2x80x9d and adding an appropriate suffix is not always followed because of the possible similarity of a resulting name to one or more substituents. Thus, a hydrocarbyl ether is referred to as a xe2x80x9chydrocarbyloxyxe2x80x9d group rather than a xe2x80x9chydrocarboxyxe2x80x9d group as may possibly be more proper when following the usual rules of chemical nomenclature. On the other hand, a hydrocarbyl group containing a xe2x80x94C(O)O xe2x80x94 functionality is referred to as a hydrocarboyl group inasmuch as there is no ambiguity in using that suffix. As a skilled worker will understand, a substituent that cannot exist such as a C1 alkenyl group is not intended to be encompassed by the word xe2x80x9chydrocarbylxe2x80x9d.
As stated before, a particularly preferred hydrocarbyl group is an alkyl group. As a consequence, a generalized, but more preferred substituent can be recited by replacing the descriptor xe2x80x9chydrocarbylxe2x80x9d with xe2x80x9calkylxe2x80x9d in any of the substituent groups enumerated herein.
Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like. Examples of suitable alkenyl radicals include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, decenyl and the like. Examples of alkynyl radicals include ethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
The term xe2x80x9ccarbonylxe2x80x9d, alone or in combination, means a xe2x80x94C(xe2x95x90O)xe2x80x94 group wherein the remaining two bonds (valences) are independently substituted. The term xe2x80x9cthiolxe2x80x9d or xe2x80x9csulfhydrylxe2x80x9d, alone or in combination, means a xe2x80x94SH group. The term xe2x80x9cthioxe2x80x9d or xe2x80x9cthiaxe2x80x9d, alone or in combination, means a thiaether group; i.e., an ether group wherein the ether oxygen is replaced by a sulfur atom.
The term xe2x80x9caminoxe2x80x9d, alone or in combination, means an amine or xe2x80x94NH2 group, whereas the term mono-substituted amino, alone or in combination, means a substituted amine xe2x80x94N(H) (substituent) group wherein one hydrogen atom is replaced with a substituent, and disubstituted amine means a xe2x80x94N(substituent)2 wherein two hydrogen atoms of the amino group are replaced with independently selected substituent groups. Amines, amino groups and amides are classes that can be designated as primary (Ixc2x0), secondary (IIxc2x0) or tertiary (IIIxc2x0) or unsubstituted, mono-substituted or di-substituted depending on the degree of substitution of the amino nitrogen. Quaternary amine (IVxc2x0) means a nitrogen with four substituents (xe2x80x94N+(substituent)4) that is positively charged and accompanied by a counter ion or N-oxide means one substituent is oxygen and the group is represented as (xe2x80x94N+(substituent)3xe2x80x94Oxe2x88x92); i.e., the charges are internally compensated.
The term xe2x80x9ccyanoxe2x80x9d, alone or in combination, means a xe2x80x94C-triple bond-N (xe2x80x94CN) group. The term xe2x80x9cazidoxe2x80x9d, alone or in combination, means a xe2x80x94N-double bond-N-double bond-N (xe2x80x94Nxe2x95x90Nxe2x95x90N) group.
The term xe2x80x9chydroxylxe2x80x9d, alone or in combination, means a xe2x80x94OH group. The term xe2x80x9cnitroxe2x80x9d, alone or in combination, means a xe2x80x94NO2 group.
The term xe2x80x9cazoxe2x80x9d, alone or in combination, means a xe2x80x94Nxe2x95x90Nxe2x80x94 group wherein the bonds at the terminal positions are independently substituted. The term xe2x80x9chydrazinoxe2x80x9d, alone or in combination, means a xe2x80x94NHxe2x80x94NHxe2x80x94 group wherein the remaining two bonds (valences) are independently substituted. The hydrogen atoms of the hydrazino group can be replaced, independently, with substituents and the nitrogen atoms can form acid addition salts or be quaternized.
The term xe2x80x9csulfonylxe2x80x9d, alone or in combination, means a xe2x80x94S(xe2x95x90O)2xe2x80x94 group wherein the remaining two bonds (valences) can be independently substituted. The term xe2x80x9csulfoxidoxe2x80x9d, alone or in combination, means a xe2x80x94S(xe2x95x90O)1- group wherein the remaining two bonds (valences) can be independently substituted. The term xe2x80x9csulfonylamidexe2x80x9d, alone or in combination, means a xe2x80x94S(xe2x95x90O)2xe2x80x94Nxe2x95x90 group wherein the remaining three bonds (valences) are independently substituted. The term xe2x80x9csulfinamidoxe2x80x9d, alone or in combination, means a xe2x80x94S(xe2x95x90O)1Nxe2x95x90 group wherein the remaining three bonds (valences) are independently substituted. The term xe2x80x9csulfenamidexe2x80x9d, alone or in combination, means a xe2x80x94Sxe2x80x94Nxe2x95x90 group wherein the remaining three bonds (valences) are independently substituted.
The term xe2x80x9chydrocarbyloxyxe2x80x9d, alone or in combination, means an hydrocarbyl ether radical wherein the term hydrocarbyl is as defined above. Examples of suitable hydrocarbyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like. The term xe2x80x9ccyclohydrocarbylxe2x80x9d, alone or in combination, means a hydrocarbyl radical that contains 3 to about 8 carbon atoms, preferably from about 3 to about 6 carbon atoms, and is cyclic. Examples of such cyclohydrocarbylhydrocarbyl radicals include cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexyl cyclooctynyl and the like. The term xe2x80x9ccyclohydrocarbylhydrocarbylxe2x80x9d means an hydrocarbyl radical as defined above which is substituted by a cyciohydrocarbyl as also defined above.
The term xe2x80x9carylxe2x80x9d, alone or in combination, means a phenyl or naphthyl radical that optionally carries one or more substituents selected from hydrocarbyl, hydrocarbyloxy, halogen, hydroxy, amino, nitro and the like, such as phenyl, p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, and the like. The term xe2x80x9carylhydrocarbylxe2x80x9d, alone or in combination, means an hydrocarbyl radical as defined above in which one hydrogen atom is replaced by an aryl radical as defined above, such as benzyl, 2-phenylethyl and the like. The term xe2x80x9carylhydrocarbyloxycarbonylxe2x80x9d, alone or in combination, means a radical of the formula xe2x80x94C(O)xe2x80x94O-arylhydrocarbyl in which the term xe2x80x9carylhydrocarbylxe2x80x9d has the significance given above. An example of an arylhydrocarbyloxycarbonyl radical is benzyloxycarbonyl. The term xe2x80x9caryloxyxe2x80x9d means a radical of the formula aryl-Oxe2x80x94 in which the term aryl has the significance given above. The term xe2x80x9caromatic ringxe2x80x9d in combinations such as substituted-aromatic ring sulfonamide, substituted-aromatic ring sulfinamide or substituted-aromatic ring sulfenamide means aryl or heteroaryl as defined above.
The terms xe2x80x9chydrocarbyloylxe2x80x9d or xe2x80x9chydrocarbylcarbonylxe2x80x9d, alone or in combination, mean an acyl radical derived from an hydrocarbylcarboxylic acid, examples of which include acetyl, propionyl, acryloyl, butyryl, valeryl, 4-methylvaleryl, and the like. The term xe2x80x9ccyclohydrocarbylcarbonylxe2x80x9d means an acyl group derived from a monocyclic or bridged cyclohydrocarbylcarboxylic acid such as cyclopropanecarbonyl, cyclohexenecarbonyl, adamantanecarbonyl, and the like, or from a benz-fused monocyclic cyclohydrocarbylcarboxylic acid that is optionally substituted by, for example, a hydrocarbyloylamino group, such as 1,2,3,4-tetrahydro-2-naphthoyl, 2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl. The terms xe2x80x9carylhydrocarbyloylxe2x80x9d or xe2x80x9carylhydrocarbylcarbonylxe2x80x9d mean an acyl radical derived from an aryl-substituted hydrocarbylcarboxylic acid such as phenylacetyl, 3-phenylpropenyl (cinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminocinnamoyl, 4-methoxycinnamoyl and the like.
The terms xe2x80x9caroylxe2x80x9d or xe2x80x9carylcarbonylxe2x80x9d means an acyl radical derived from an aromatic carboxylic acid. Examples of such radicals include aromatic carboxylic acids, an optionally substituted benzoic or naphthoic acid such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl, 2-naphthoyl, 6-carboxy-2 naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like.
The heterocyclyl (heterocyclo) or heterocyclohydrocarbyl portion of a heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylhydrocarbyloxycarbonyl, or heterocyclohydrocarbyl group or the like is a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle that contains one to four hetero atoms selected from nitrogen, oxygen and sulphur, which is optionally substituted on one or more carbon atoms by a halogen, alkyl, alkoxy, oxo group, and the like, and/or on a secondary nitrogen atom (i.e., xe2x80x94NHxe2x80x94) by an hydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloyl, aryl or arylhydrocarbyl or on a tertiary nitrogen atom (i.e. xe2x95x90Nxe2x80x94) by oxido and that is attached via a carbon atom. The tertiary nitrogen atom with three substituents can also form a N-oxide [xe2x95x90N(O)xe2x80x94] group. Examples of such heterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, and the like.
The heteroaryl portion of a heteroaroyl, heteroaryloxycarbonyl, or a heteroarylhydrocarbyloyl (heteroarylhydrocarbyl carbonyl) group or the like is an aromatic monocyclic, bicyclic, or tricyclic heterocycle that contains the hetero atoms and is optionally substituted as defined above with respect to the definition of heterocyclyl. A xe2x80x9cheteroarylxe2x80x9d group is an aromatic heterocyclic ring substituent that can contain one, two, three or four atoms in the ring that are other than carbon. Those heteroatoms can be nitrogen, sulfur or oxygen. A heteroaryl group can contain a single five- or 6-membered ring or a fused ring system that contains two 6-membered rings or a five- and a 6-membered ring. Exemplary heteroaryl groups include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as 1,3,5-, 1,2,4- or 1,2,3-triazinyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl groups; six/5-membered fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl and anthranilyl groups; and six/6-membered fused rings such as 1,2-, 1,4-,2,3- and 2,1-benzopyronyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1,4-benzoxazinyl groups.
The term xe2x80x9ccyclohydrocarbylhydrocarbyloxycarbonylxe2x80x9d means an acyl group derived from a cyclohydrocarbylhydrocarbyloxycarboxylic acid of the formula cyclohydrocarbylhydrocarbyl-Oxe2x80x94COOH wherein cyclohydrocarbylhydrocarbyl has the significance given above. The term xe2x80x9caryloxyhydrocarbyloylxe2x80x9d means an acyl radical of the formula aryl-O-hydrocarbyloyl wherein aryl and hydrocarbyloyl have the significance given above. The term xe2x80x9cheterocyclyloxycarbonylxe2x80x9d means an acyl group derived from heterocyclyl-Oxe2x80x94COOH wherein heterocyclyl is as defined above. The term xe2x80x9cheterocyclylhydrocarbyloylxe2x80x9d is an acyl radical derived from a heterocyclyl-substituted hydrocarbylcarboxylic acid wherein heterocyclyl has the significance given above. The term xe2x80x9cheterocyclylhydrocarbyloxycarbonylxe2x80x9d means an acyl radical derived from a heterocyclyl-substituted hydrocarbyl-Oxe2x80x94COOH wherein heterocyclyl has the significance given above. The term xe2x80x9cheteroaryloxycarbonylxe2x80x9d means an acyl radical derived from a carboxylic acid represented by heteroaryl-Oxe2x80x94COOH wherein heteroaryl has the significance given above.
The term xe2x80x9caminocarbonylxe2x80x9d alone or in combination, means an amino-substituted carbonyl (carbamoyl) group derived from an amino-substituted carboxylic acid wherein the amino group can be a primary, secondary or tertiary amino group containing substituents selected from hydrogen, hydrocarbyl, aryl, aralkyl, cyclohydrocarbyl, cyclohydrocarbylhydrocarbyl radicals and the like. The ter, xe2x80x9caminohydrocarbyloylxe2x80x9d means an acyl group derived from an amino-substituted hydrocarbylcarboxylic acid wherein the amino group can be a primary, secondary or tertiary amino group containing substituents independently selected from hydrogen, alkyl, aryl, aralkyl, cyclohydrocarbyl, cyclohydrocarbylhydrocarbyl radicals and the like.
The term xe2x80x9chalogenxe2x80x9d means fluorine, chlorine, bromine or iodine. The term xe2x80x9chalohydrocarbylxe2x80x9d means a hydrocarbyl radical having the significance as defined above wherein one or more hydrogens are replaced with a halogen. Examples of such halohydrocarbyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like. The term perfluorohydrocarbyl means a hydrocarbyl group wherein each hydrogen has been replaced by a fluorine atom. Examples of such perfluorohydrocarbyl groups, in addition to trifluoromethyl above, are perfluorobutyl, perfluoroisopropyl, perfluorododecyl and perfluorodecyl.
Table 1 through Table 50, below, show several contemplated aromatic sulfonyl alpha-hydroxy hydroxamic acid compounds as structural formulas that illustrate substituent groups. Each group of compounds is illustrated by a generic formula, followed by a series of preferred moieties or groups that constitute various substituents that can be attached at the position clearly shown in the generic structure. The substituent symbols, e.g., R1, are as shown in each Table. One bond (straight line) is shown with those substituents to indicate the respective positions of attachment in the illustrated compound. This system is well known in the chemical communication arts and is widely used in scientific papers and presentations.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Process
A process for treating a host mammal having a condition associated with pathological matrix metalloprotease activity is also contemplated. That process comprises administering a compound described hereinbefore in an MMP enzyme-inhibiting effective amount to a mammalian host having such a condition. The use of administration repeated a plurality of times is particularly contemplated.
A contemplated compound is used for treating a host mammal such as a mouse, rat, rabbit, dog, horse, primate such as a monkey, chimpanzee or human that has a condition associated with pathological matrix metalloprotease activity.
Also contemplated is the similar use of a contemplated compound in the treatment of a disease state that can be affected by the activity of metalloproteases such as TNF-A convertase. Exemplary of such disease states are the acute phase responses of shock and sepsis. coagulation responses, hemorrhage and cardiovascular effects, fever and inflammation, anorexia and cachexia.
In treating a disease condition associated with pathological matrix metalloproteinase activity, a contemplated MMP inhibitor compound can be used, where appropriate, in the form of an amine salt derived from an inorganic or organic acid. Exemplary acid salts include but are not limited to the following; acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoate.
Also, a basic nitrogen-containing group can be quaternized with such agents as lower alkyl (C1-C6) halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibuytl, and diamyl sulfates, long chain (C8-C20) halides such as decyl, lauryl, myristyl and dodecyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others to provide enhanced water-solubility. Water or oil-soluble or dispersible products are thereby obtained as desired. The salts are formed by combining the basic compounds with the desired acid.
Other compounds useful in this invention that are acids can also form salts. Examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases or basic quaternary ammonium salts.
In some cases, the salts can also be used as an aid in the isolation, purification or resolution of the compounds of this invention.
Total daily dose administered to a host mammal in single or divided doses of an MMP enzyme-inhibiting effective amount can be in amounts, for example, of about 0.001 to about 100 mg/kg body weight, preferably about 0.001 to about 30 mg/kg body weight daily and more usually about 0.01 to about 10 mg. Dosage unit compositions can contain such amounts or submultiples thereof to make up the daily dose. A suitable dose can be administered, in multiple sub-doses per day. Multiple doses per day can also increase the total daily dose, should such dosing be desired by the person prescribing the drug.
The dosage regimen for treating a disease condition with a compound and/or composition of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized and whether the compound is administered as part of a drug combination. Thus, the dosage regimen actually employed can vary widely and therefore can deviate from the preferred dosage regimen set forth above.
A compound useful in the present invention can be formulated as a pharmaceutical composition. Such a composition can then be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration can also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. Formulation of drugs is discussed in, for example, Hoover, John E., Remington""s Pharmaceutical Sciences, Mack Publishing Co. (Easton, Pa.: 1975) and Liberman, H. A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker (New York, N.Y.: 1980).
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer""s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic monoor diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Dimethyl acetamide, surfactants including ionic and non-ionic detergents, polyethylene glycols can be used. Mixtures of solvents and wetting agents such as those discussed above are also useful.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter, synthetic mono- di- or triglycerides, fatty acids and polyethylene glycols that are sold at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration can include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds can be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets can contain a controlled-release formulation as can be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents such as sodium citrate, magnesium or calcium carbonate or bicarbonate. Tablets and pills can additionally be prepared with enteric coatings.
For therapeutic purposes, formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the mammalian host treated and the particular mode of administration.
Preparation of Useful Compounds
Schemes I-IV and 1-2C hereinbelow illustrate general and specific chemical processes and transformations that can be useful for the preparation of compounds useful in this invention; i.e., compounds of Formulas I-IV, with particular emphasis on compounds of Formulas II and IV and similar inhibitors.
A compound of the invention can be produced in accordance with the following synthetic schemes: 
 
 
 
 
Schemes I through IV illustrate general procedures and examples of chemical transformations useful for the preparation of compounds of this invention. Scheme I starts with the conversion of a protected carboxylic acid into a alpha-beta unsaturated protected carboxylic acid wherein R2 and R1 are as defined hereinabove. The preferred reagents are bis-halogenated methanes such as methylene iodide. Bases can be in several categories such as are discussed below. Preferred bases are strong, hindered and/or non-nucleophilic organic bases such metal amides, lithium alkyls or metal hydrides. Preferred solvents are aprotic solvents or dipolar aprotic solvents as discussed below. Most preferred are dipolar aprotic solvents such as DMF.
P represents a carboxylic acid protecting group such as an ester or an acid. P can also represent an xe2x80x94OH group depending upon conditions that are readily recognized by a person skilled in the art.
The double bond compounds produced by this procedure can be oxidized to epoxides. Oxidation can be direct as with, for example, per-acids or hydrogen peroxide or other similar oxidizing agents such as those discussed below. Halohydrin formation with HOCl or halogenation with a halogen such as chlorine or bromine followed by, for example, base treatment with a metal hydroxide, can also lead to the desired epoxide by methods well known in the art. In addition, a Darzens type reaction (glycidic acid derivative formation) wherein a alpha-halo carbonyl compound such as a alpha-chloro carboxylic ester is treated with an aldehyde or ketone in the presence of base to form the epoxide directly. Preferred bases are non-nucleophilic or moderately nucleophilic bases such as metal alcoholates, metal amides, magnesium reagents, lithium reagents or metal hydrides as discussed below.
Scheme I also illustrates opening of an exemplary epoxide intermediate of this invention using a nucleophilic thiol or thiolate reagent. Thiolate nucleophiles can be created by methods well known in the art such as treating a thiol with base in situ or by using a preformed thiolate. Use of a pre-formed thiolate can allow maintenance of a protecting group. These methods are further discussed below as part of our discussion of the Michael reaction. A preferred base is potassium hydroxide if hydrolysis of the protecting group is desired or, for example, a alcoholate such as sodium methoxide if a methyl ester protecting group is to be maintained in use or an alkyl lithium or lithium amide if maintaining a protecting group is desired.
The product of the nucleophilic ring opening reaction (epoxide ring opening) can be oxidized to the sulfone in one step using two equivalents of oxidizing agent. The starting material for this reaction can be a sulfide wherein P is a protecting group such as an ester or amide or a carboxylic acid or where P is OH. Reagents for this process can include peroxymonosulfate OXONE(copyright)), hydrogen peroxide, meta-chloroperbenzoic acid, perbenzoic acid, peracetic acid, perlactic acid, tert-butyl peroxide, tert-butyl hydroperoxide, tert-butyl hypochlorite, sodium hypochlorite, hypochlorous acid, sodium meta-periodate, periodic acid and the like. Protic, non-protic, dipolar aprotic solvents, either pure or mixed, can be chosen, for example, methanol/water.
The oxidation can be carried out at temperature of about xe2x88x9268xc2x0 to about 50xc2x0 degrees centigrade and normally selected from a range xe2x88x9210xc2x0 C. to about 40xc2x0 C. This oxidation can be carried out in two steps via the synthesis of sulfoxide which requires the use of only about one equivalent of one of the above oxidizing agents preferable at about zero degrees C. The solvents listed above can be used with these selective oxidations to a sulfoxide with, for example, methanol or methanol/water being preferred along with a temperature of from about xe2x88x9210xc2x0 C. to 30xc2x0 C. It can be desirable in the case of more active oxidizing agents, but not required, that the reactions be carried out under an inert gas atmosphere with or without degassed solvents. The sulfoxide is then oxidized to the sulfone with a second equivalent of oxidizing agent in a separate step that can be carried out at a stage of the synthesis chosen by a person skilled in the art. Again, at this stage of the synthesis of the product compounds, the person skilled in the art can elect to either keep or remove the protecting group by the choice of reagents, solvents and pH conditions. For example, protic solvents or mixed solvents such as water or water/solvent mixtures under basic conditions can produce the acid directly whereas some peroxy acids in non-protic or dipolar aprotic solvents can oxidize the sulfur without removing the protecting group. A preferred oxidizing regent is peroxymonosulfate with the reaction carried out under conditions wherein the preferred protecting group, a methyl ester, is hydrolyzed.
Scheme I also illustrates hydroxamate formation to prepare the hydroxamic acid products of this invention. The preferred method in this case is direct reaction with hydroxylamine (aq) of an activated ester and diimide coupling. A second preferred method is exchange with, for example, a methyl ester. This type of reaction is well known in the art especially the peptide synthesis art and is discussed further below.
Scheme II illustrates the Michael reaction of a thiol such as R1SH with a protected alpha-beta unsaturated carboxylic acid to form the products of this invention; i.e., a sulfide amide or ester wherein the amide or ester are serving as the carboxylic acid protecting groups. This reaction can be base mediated by the use of catalytic amounts of some bases or carried out with an equivalent or more of a base or by the addition of a preformed thiolate reagent such as a preformed thiol salt.
Non-limiting examples include sodium, potassium, lithium, calcium, or magnesium salts of thiophenol, substituted thiophenols or heteroarylthiols as defined above. Bases that can be used include, for example, metal hydroxides such as sodium, potassium, lithium or magnesium hydroxide, oxides such as those of sodium, potassium, lithium, calcium or magnesium, metal carbonates such as those of sodium, potassium, lithium, calcium or magnesium, metal bicarbonates such as sodium bicarbonate or potassium bicarbonate, Ixc2x0, IIxc2x0 or IIIxc2x0 organic amines such as alkyl amines, arylalkyl amines, alkylarylalkyl amines, heterocyclic amines or heteroaryl amines, ammonium hydroxides or quaternary ammonium hydroxides. As non-limiting examples. such amines can include triethyl amine, trimethyl amine, diisopropyl amine, methyldiisopropyl amine, diazabicyclononane, tribenzyl amine, dimethylbenzyl amine, morpholine, N-methylmorpholine, N,Nxe2x80x2-dimethylpiperazine, N-ethylpiperidine, 1,1,5,5-tetramethylpiperidine, dimethylaminopyridine, pyridine, quinoline,.tetramethylethylenediamine and the like. Non-limiting examples of ammonium hydroxides, usually made from amines and water, can include ammonium hydroxide, triethyl ammonium hydroxide, trimethyl ammonium hydroxide, methyldiiospropyl ammonium hydroxide, tribenzyl ammonium hydroxide, dimethylbenzyl ammonium hydroxide, morpholinium hydroxide, N-methylmorpholinium hydroxide, N,Nxe2x80x2-dimethylpiperazinium hydroxide, N-ethylpiperidinium hydroxide, and the like. As non-limiting examples, quaternary ammonium hydroxides can include tetraethyl ammonium hydroxide, tetramethyl ammonium hydroxide, dimethyldiiospropyl ammonium hydroxide, benzylmethyldiisopropyl ammonium hydroxide, methyldiazabicyclononyl ammonium hydroxide, methyltribenzyl ammonium hydroxide, N,N-dimethylmorpholinium hydroxide, N,N,Nxe2x80x2,Nxe2x80x2,-tetramethylpiperazenium hydroxide, and N-ethyl-Nxe2x80x2-hexylpiperidinium hydroxide and the like. Metal hydrides, amide or alcoholates such as calcium hydride, sodium hydride, potassium hydride, lithium hydride, sodium methoxide, potassium tert-butoxide, calcium ethoxide, magnesium ethoxide, sodium amide, potassium diisopropyl amide and the like can also be suitable reagents. Organometallic deprotonating agents such as alkyl or aryl lithium reagents such as methyl, phenyl or butyl lithium, Grignard reagents such as methylmagnesium bromide or methymagnesium chloride, organocadium reagents such as dimethylcadium and the like can also serve as bases for causing salt formation or catalyzing the reaction. Quaternary ammonium hydroxides or mixed salts are also useful for aiding phase transfer couplings or serving as phase transfer reagents.
The reaction media can consist of a single solvent, mixed solvents of the same or different classes or serve as a reagent in a single or mixed solvent system. The solvents can be protic, non-protic or dipolar aprotic.
Non-limiting examples of protic solvents include water, methanol (MeOH), denatured or pure 95% or absolute ethanol, isopropanol and the like. Typical non-protic solvents include acetone, tetrahydrofurane (THF), dioxane, diethylether, tert-butylmethyl ether (TBME), aromatics such as xylene, toluene, or benzene, ethyl acetate, methyl acetate, butyl acetate, trichloroethane, methylene chloride, ethylenedichloride (EDC), hexane, heptane, isooctane, cyclohexane and the like. Dipolar aprotic solvents include compounds such as dimethylformamide (DMF), dimethylacetamide (DMAc), acetonitrile, nitromethane, tetramethylurea, N-methylpyrrolidone and the like. Non-limiting examples of reagents that can be used as solvents or as part of a mixed solvent system include organic or inorganic monoor multi-protic acids or bases such as hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, triethylamine, morpholine, N-methylmorpholine, piperidine, pyrazine, piperazine, pyridine, potassium hydroxide, sodium hydroxide, alcohols or amines for making esters or amides or thiols for making the products of this invention and the like.
Room temperature or less or moderate warming (xe2x88x9210xc2x0 C. to 60xc2x0 C.) are the preferred temperatures of the reaction. If desired, the reaction temperature can be about xe2x88x9276xc2x0 C. to the reflux point of the reaction solvent or solvents.
The beta-SR1 derivative prepared as discussed above can then be carried forward as such or oxidized to the corresponding sulfone by methods discussed above. Either of these products can then be reacted under condensation reaction conditions with an aldehyde or ketone wherein R6 and R7 can be, independently, hydrogen or the groups represented by R2 with one less carbon atom; i.e., that carbon atom illustrated in the structures that is directly attached to the carbon atom alpha to the carbonyl group. This produces the unsaturated sulfide or sulfone containing carboxylic acids or protected carboxylic acids illustrated in Scheme II.
The alpha-beta unsaturated sulfide can be oxidized to the sulfone following the condensation as is shown in the scheme. Oxidation of either of unsaturated sulfide or sulfone containing carboxylic acids or protected carboxylic acids to the epoxide containing analogs is also illustrated. Oxidation of the sulfide can produce both the epoxide ring and the sulfone in one step.
Hydroxylation of the double bond is also illustrated in Scheme II. This process is well known in the art and examples reagents for such conversions include osmium tetroxide, permanganate salts including hydroxide if desired, iodine with lead acetate, halohydrin formation followed by displacement of the halogen with base or its conversion into an epoxide followed by ring opening with hydroxide or catalytic osmium tetroxide in the presence of an agent such as N-methyl-morpholine-N-oxide (NMM-N-oxide) for its recycling in situ (re-oxidation) to the tetroxide.
The Schemes illustrate conversion of sulfides or sulfones into hydroxamic acid derivatives wherein P is hydrogen or a protected intermediate such as an O-arylalkylether, acyl or O-cycloalkoxyalkylether group. In the case of compounds where P=H, treatment with one or more equivalents of hydroxylamine hydrochloride at room temperature or above in a solvent or solvents such as those listed above can provide hydroxamic acid compounds of this invention directly. There can be an exchange process also such as that between a methyl ester and a hydroxylamine that can be further catalyzed by the addition of additional acid. Alternatively, a base such as a salt of an alcohol used as a solvent, for example, sodium methoxide in methanol, can be used to form hydroxylamine in situ which can exchange with an ester-or amide.
The exchange can also be carried out with a protected hydroxyl amine such as tetrahydropyranylhydroxyamine (THPONH2), benzylhydroxylamine (BnONH2), and the like in which case compounds wherein P is tetrahydropyranyl (THP) or benzyl (Bn) are the products. Removal of the protecting groups when desired, for example, following further transformations in another part of the molecule or following storage, is accomplished by standard methods well known in the art such as acid hydrolysis of the THP group or reductive removal of the benzyl group with hydrogen and a metal catalyst such as palladium, platinum, platinum oxide, palladium on carbon or nickel.
Alternatively, the carboxylic acids of this invention can be converted into activated carbonyl compounds using reagents well known in the art including the peptide and protein synthesis and amino acid coupling or conjugation art. Examples of such reagents are thionyl chloride, oxalyl chloride, phosphorus oxychloride, HOBT, isobutylchloroformate an the like with or without the use of intermediate condensing agents (carbonyl activating) such as the diimides. These valuable activated carbonyl intermediates (acid chlorides, mixed anhydrides and the like) can then be transformed into hydroxamic acids or hydroxamic acid derivatives such as those where P is H, benzyl or THP by condensation with hydroxyl amine or the O-protected hydroxyl amine derivative.
The carboxylic acids of this invention can be prepared and used directly or, as mentioned above, in a protected form. Protected groups for carboxylic acids are well known in the art and include such functional groups as esters, amides, ortho-esters, and groups generally known as ethers such as tetrahydropyranyl ethers or tetrahydropyranyl esters. Alkyl esters such as methyl, ethyl or tert-butyl esters and aralkyl esters such as benzyl, benzhydryl and trityl esters are well known in the art as is their preparation and removal. Amides, either primary, secondary or tertiary, are also well known in the art as are their preparation and removal. Many amides and esters are commercially available. The preferred protecting group is the methyl ester and the preferred method of conversion of the ester into the acid is via base hydrolysis or the use of a basic reagent or basic conditions in a particular reaction wherein this conversion is performed in situ in a single vessel.
Scheme III illustrates another general method of synthesis of the sulfone containing carbonyl compounds of this invention; i.e., use of the SN2 class of reactions. A bimolecular nucleophilic displacement (SN2) reaction is illustrated where an epoxide ring is opened or an activated hydroxyl group derivative of a diol is displace or where an alcohol is converted into a nucleophilic salt (hydroxyl anion salt) by a base. In the latter example, a preparation of the compounds of this invention wherein R2 is methoxyalkyl is by conversion of a hydroxyl group into it alkoxide anion as can be done with base treatment and preferably using a non-nucleophilic base such as sodium hydride, calcium hydride, potassium hydride or an alkyl lithium or amide reagent. A preferred base is sodium hydride. A preferred electrophile; i.e., compound undergoing nucleophilic attack, is an methyl halide or organic sulfonate methyl ester. The most preferred electrophile is methyl iodide. The solvents, solvent mixtures or solvent/reagent mixtures discussed are satisfactory but non-protic or dipolar aprotic solvents such as acetone, acetonitrile, DMF and the like are examples of a preferred class. Salts of these amines can be prepared by standard methods known in the art, e.g., treatment of an amine with HCl to form a hydrochloride salt.
Other SN2 used in the preparation of compounds of this invention involve conversion of an alcohol of the diols shown in the schemes into a electrophile such as a halide or a organic sulfonate ester. Examples of halides are chlorides, bromides or iodides and their preparation is well known in the art. Examples of organic sulfonate esters include tosylates, benzene sulfonates, camphorsulfonates, mesylates and triflates and their preparation is well known in the art. Preferred halides are bromides and preferred sulfonates are trifluoromethanesulfonates (triflates). An example of a method of preparing a halide is treatment of a double bone with a hypohalite or opening an epoxide ring with a hydrohalic acid such as HBr, HCl or HI. An example of a method of preparing a sulfonate ester is treatment of the alcohol with a base such as a tertiary amine or hindered or non-nucleophilic base as discussed above to form an alkoxide anion followed by the addition of a sulfonic acid anhydride or chloride such as triflic anhydride or methanesulfonyl chloride. Displacement (SN2) of the halide or sulfonate leaving group with ammonia, an alkyl amine, a di-alkylamine, morpholine, pyrrolidine or thiomorpholine can provide compounds of this invention. Preferred solvents for these reactions are listed above and include dipolar aprotic solvents such as DMF.
The selection of an atmosphere for the reactions of this Scheme as well as the other Schemes depends, as usual, a number of variables known to those skilled in the art. The choices can be an inert atmosphere such as nitrogen, argon, helium and the like or normal or dry air. Preferred is the use of an inert atmosphere if there is an uncertantity as to the requirements of the process. One of these variables particularly requiring the attention of the skilled person is control of oxidation by air or another means of a thiol or the salt of a thiol to its corresponding disulfide or mixed disulfide. The used of a damp atmosphere while carrying out an organometallic compound requiring synthesis not desirable for either economic or safety reasons whereas the use of air is normal for aqueous hydrolysis or exchange reactions where oxidation, for example, is not probable.
Protecting groups are used as desired in the preparation of the compounds of this invention and are discussed above. However, the decision to use protecting groups or not as well as the selection of which protecting group to use for a particular functional group is based on a particular objective and is made by a person of ordinary skill in the art. For example, a factor in the choice of a methyl ester and tert-butyl ester for the protection of a particular carboxylic acid function will vary depending upon the preferred method of preparation and the preferred method removal. For example, a methyl ester is known to be readily hydrolyzed by base or exchanged by an amine or hydroxyl amine whereas a tert-butyl ester is relatively resistant to removal by base or exchange but readily removed by acids. Such protecting groups can include acyl groups, carbamoyl groups, ethers, alkoxyalkyl ethers, cycloalkyloxy ethers, arylalkyl groups trisubstituted silyl groups and the like. Examples of such protecting groups include acetyl, THP, Benzyl, Z (benzyloxycarbonyl), tert-butyldimethylsilyl (TBDMS) groups and the like. Protecting groups are discussed in, for example, Green, T., xe2x80x9cProtecting Groups in Organic Chemistryxe2x80x9d, and other review papers and in other books.
Optically active compound isomers as well as mixed or non-optically active compound isomers are specifically intended to be included in this discussion and as part of this invention. Examples of isomers are RS isomers, enantiomers, diastereomers, racemates, cis isomers, trans isomers, E isomers, Z isomers, syn-isomers, anti-isomers, tautomers and the like. Aryl, heterocyclo or heteroaryl tautomers, heteroatom isomers and ortho, meta or para substitution isomers are also included as isomers. Solvates or solvent addition compounds such as hydrates or alcoholates are also specifically included both as chemicals of this invention and in, for example, formulations or pharmaceutical compositions for delivery. 
 
 
 
 
Best Mode for Carrying Out The Invention
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limiting of the remainder of the disclosure in any way whatsoever.